S250: CHOLINERGIC SIGNALS PROMOTE THE QUIESCENCE OF NORMAL OR LEUKAEMIC STEM CELLS THROUGH THE ACTIVATION OF ALPHA 7-NICOTINIC RECEPTOR IN BONE MARROW MESENCHYMAL STROMAL CELLS
Authors: C. Fielding, A. García-García, C. Korn, S. Gadomski, Z. Fang, C. Kapeni, J. L. Reguera, J. A. Pérez-Simón, B. Göttgens, S. Méndez-Ferrer
Journal: HemaSphere (2022)

Background: Our recent research has suggested that the sympathetic nervous system, a master regulator or homeostasis and stress responses, regulates the activity of hematopoietic stem cells (HSCs) in different bone marrow niches. We recently showed that chemotherapy or irradiation, which are routinely used for cancer treatment or as conditioning regimens for HSC transplantation, increase the release of cholinergic signals by sympathetic neurons and osteolineage cells. As a result, not all HSCs become activated (which could cause their exhaustion), but some remain quiescent, thereby retaining their full potential. Cholinergic signals activate α7 nicotinic receptor (α7nAChR) in bone marrow mesenchymal stromal cells (BMSCs), which in turn preserve stem cell quiescence under proliferative stress (Nat Commun 13:543). In addition, α7nAChR signalling exhibits anti-inflammatory properties (PMID:32595942). However, whether this signalling pathway influences acute myeloid leukaemia (AML) development and response to treatment is unclear. Aims: Investigate the influence of cholinergic signals on leukaemogenesis and therapy response in AML. Methods: Analysis of bone marrow (BM) from mouse models lacking sympathetic cholinergic innervation or α7nAChR in BMSCs, transplanted with BM cells from an inducible MLL-AF9+ AML model (Cancer Cell 15:791) and treated with cytarabine. Flow cytometry, histology, FACS, qRT-PCR. Results: We confirmed reduced density of sympathetic noradrenergic innervation in the BM of AML mice; however, interestingly, the cholinergic innervation, which also has sympathetic origin (Cell Stem Cell, in press) was preserved. To investigate the role of these fibres in AML development, we utilised a mouse model lacking sympathetic cholinergic innervation due to loss of the neurotrophic receptor GFRα2. AML developed faster in cholinergic-neural-deficient mice, compared with WT mice, transplanted with iMLL-AF9+ BM cells. This was associated with reduced quiescence of leukaemia-initiating cells (LIC) upon acute cytarabine treatment of mice lacking cholinergic skeletal innervation. This effect was more pronounced after repeated cytarabine treatment, leading to increased proliferation of LICs and augmented leukaemia burden at relapse. Given that α7nAChR transduces the cholinergic regulation of normal HSCs by BMSCs, we utilised LepR-Cre;Chrna7f/f mice to conditionally delete this signalling pathway in leukaemic mice. Reproducing the observations in mice lacking cholinergic innervation, α7nAChR deletion in BMSCs accelerated AML development, and repeated treatment with cytarabine further increased LIC proliferation, spleen infiltration and leukaemia burden after relapse. Summary/Conclusion: These results suggest that cholinergic signals increase the quiescence of normal or leukaemic stem cells through the activation of a7-nicotinic receptor in BMSCs and might influence AML response to chemotherapy.